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Praze","doi-asserted-by":"publisher","award":["GAUK \u2013 216225"],"award-info":[{"award-number":["GAUK \u2013 216225"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      A single recurrent variant, NM_004974.4(\n                      <jats:italic>KCNA2<\/jats:italic>\n                      ):c.881G&gt;A:p.(Arg294His), causes hereditary spastic paraplegia (HSP) through a unique variant\u2010specific mechanism. Data from paralogous variants suggest that this may be a druggable mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The objective of this work is to give an overview of the clinical spectrum and course of\n                      <jats:italic>KCNA2<\/jats:italic>\n                      \u2010p.(Arg294His)\u2010associated HSP (HSP\u2010\n                      <jats:italic>KCNA2<\/jats:italic>\n                      ) and report treatment with eplerenone, a potassium\u2010sparing diuretic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this retrospective study, we recruited individuals with the variant of interest through international rare disease networks. Treatment with eplerenone was done as off\u2010label use, and outcome measures were recorded during routine clinical care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We report the clinical characteristics of 23 individuals from 17 families with HSP\u2010\n                      <jats:italic>KCNA2<\/jats:italic>\n                      . We observed a consistent core phenotype of abnormal evoked potentials (100%), cerebellar ataxia (83%), and lower limb spasticity (70%). Childhood\u2010onset was more commonly associated with epilepsy (odds ratio, 4.16;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.042), and 52% had developmental delay. Progression of motor disability was slow even in childhood onset. We observed full (100%) penetrance and estimated the prevalence to be 0.18 to 0.69 case per million. Treatment with eplerenone was associated with a decrease on the Scale for the Assessment and Rating of Ataxia (Cohen's\n                      <jats:italic>d<\/jats:italic>\n                      \u2009=\u2009\u22121.8; \u22127.9% change from baseline,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.015), but not on the Spastic Paraplegia Rating Scale, whereas stopping treatment was associated with worsening symptoms. At 2\u2010year follow\u2010up, four of five (80%) individuals chose to remain on treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      HSP\u2010\n                      <jats:italic>KCNA2<\/jats:italic>\n                      is a syndrome with a recognizable variant\u2010specific core phenotype. Our exploratory analyses on eplerenone may serve as rationale for future investigations on targeted treatments. \u00a9 2026 International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70555","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:19:07Z","timestamp":1791440347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>KCNA2<\/i>\n                    <\/scp>\n                    \u2010Associated Hereditary Spastic Paraplegia: Clinical Characteristics and Rationale for Targeted Treatment"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1596-5599","authenticated-orcid":false,"given":"Christian M.","family":"Bo\u00dfelmann","sequence":"first","affiliation":[{"name":"Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research and Hertie Center of Neurology University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-4932","authenticated-orcid":false,"given":"Martin","family":"Vyhnalek","sequence":"additional","affiliation":[{"name":"Center of Hereditary Ataxias, Department of Neurology, Second Faculty of Medicine Charles University and Motol University Hospital  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Blichova","sequence":"additional","affiliation":[{"name":"Center of Hereditary Ataxias, Department of Neurology, Second Faculty of Medicine Charles University and Motol University Hospital  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9163-6486","authenticated-orcid":false,"given":"Ludmila","family":"Novotna","sequence":"additional","affiliation":[{"name":"Center of Hereditary Ataxias, Department of Neurology, Second Faculty of Medicine Charles University and Motol University Hospital  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6186-5142","authenticated-orcid":false,"given":"Anna Uhrova","family":"Meszarosova","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Neurogenetic Laboratory, Second Faculty of Medicine Charles University and University Hospital Motol  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7731-5129","authenticated-orcid":false,"given":"Petra","family":"Havr\u00e1nkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Neurology and Centre of Clinical Neuroscience First Faculty of Medicine and General University Hospital in Prague, Charles University  Prague Czech 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(SyNergy)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-8377","authenticated-orcid":false,"given":"Georgios","family":"Koutsis","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology National and Kapodistrian University of Athens, Eginitio Hospital  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7003-5717","authenticated-orcid":false,"given":"Georgia","family":"Karadima","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology National and Kapodistrian University of Athens, Eginitio Hospital  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5753-2687","authenticated-orcid":false,"given":"Ainara","family":"Salazar\u2010Villacorta","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders UCL Queen Square Institute of Neurology  London UK"},{"name":"Developmental Neurosciences, Zayed Centre for Research, UCL Great Ormond Street Institute of Child Health, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin A.","family":"Ellis","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Scheper","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Children's Hospital Auf der Bult  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9033-3743","authenticated-orcid":false,"given":"Dieter","family":"Gl\u00e4ser","sequence":"additional","affiliation":[{"name":"MVZ Genetikum GmbH  Neu\u2010Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-4836","authenticated-orcid":false,"given":"Tobias B.","family":"Haack","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics University of T\u00fcbingen  T\u00fcbingen 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